KR20080095130A - Manufacture and Application of Drug Carrier Using pH Sensitive Block Copolymer - Google Patents

Abstract

The present invention relates to a drug carrier comprising a hydrophilic moiety and a hydrophilic moiety having a hydrophilic moiety and a hydrophobic moiety containing a hydrophobic moiety. Specifically, the drug carrier of the present invention has high sensitivity to pH, and thus, various cancers or At the locally low pH of the inflammatory disease site, the drug carrier readily disintegrates, releasing a large amount of drug to the disease site in a short time to deliver the drug, thereby enhancing the therapeutic efficacy of the drug and significantly reducing the toxicity of the drug itself. It is useful for the treatment of various cancers or inflammatory diseases.

Description

Preparation and application of drug carrier using H sensitive block copolymer TECHNICAL FIELD

Figure 1a illustrates the structural formula of the pH sensitive block copolymer of the present invention,

1B is a diagram showing a schematic diagram of micelle particles obtained by encapsulating a hydrophobic drug in an amphiphilic pH-sensitive block copolymer,

2 is a TEM image of micelles consisting of pH-sensitive polymers MPEG-HPAE (a) and MPEG-OPAE (c), drug-enclosed DOX-MPEG-HPAE (b) and DOX-MEPG-OPAE micelle (d) A photo showing a TEM image.

Figure 3 is a graph showing the results of the measurement of the drug release from micelle according to the pH value over time in the micelle consisting of the pH-sensitive block copolymer encapsulated drug prepared in Example 2,

Figure 4 is a fluorescent image comparing the degree of intracellular absorption of doxorubicin-encapsulated pH-sensitive DOX-MPEG-HPAE micelles at different pH conditions,

5A-5C show cancer growth inhibition graph (FIG. 5A), weight change graph (FIG. 5B) and survival rate (FIG. 5C) of pH sensitive DOX-MPEG-HPAE loaded with doxorubicin.

The present invention relates to a drug carrier consisting of a pH-sensitive block copolymer containing a hydrophobic drug, specifically, the drug carrier is easily collapsed due to low pH of cancer and inflammatory disease sites, so that a high concentration of the drug carrier is specifically The present invention relates to a pH-sensitive drug carrier and its use that can increase the efficacy of a drug by delivering the drug and at the same time significantly lower the toxicity to the drug itself.

Pharmacologically effective drugs (eg anticancer drugs) did not perform as expected, due to the serious toxicity and low solubility of the drug in actual clinical applications. Therefore, new drug formulations have been actively developed to minimize side effects of drugs used to treat diseases.

Drug delivery agents such as nanoparticles, micelles, and microspheres have been developed that can minimize drug toxicity while improving the therapeutic efficacy of drugs. For example, micelles having a thermodynamically stable and uniform spherical structure in a compound having both hydrophilic and hydrophobic residues are present. The compound having the micelle structure is hydrophobic on the central portion thereof, and thus may contain various hydrophobic drugs. In addition, hydrophobic drugs have the disadvantage of low solubility in aqueous solution, but when encapsulated in micelle particles can improve drug solubility in aqueous solution. In other words, nanoscale micelles composed of hydrophobic and hydrophilic residues have high potential for drug delivery.

Nanoparticles are surrounded by hydrophilic materials and protected from various immune mechanisms in the body, and are designed to enclose hydrophobic drugs in their inner core. Such nanoparticles can be selectively targeted to cancer or inflammatory disease tissue sites. This is because blood vessels in most cancerous or inflammatory disease tissues are looser than other normal tissues, and nanoparticles of appropriate size can easily accumulate around cancerous or inflammatory disease tissues by an enhanced permeability and retention (EPR) effect. In addition, they induce prolonged residence time and increased targeting rate of anticancer drugs, thereby reducing side effects and increasing bioavailability.

However, it was difficult to expect an increased anticancer effect because the release rate of the enclosed anticancer agent could not be controlled.

On the other hand, the pH environment in normal tissues and the body generally maintains pH 7.2-pH 7.4. However, in cancer or inflammatory disease tissues, the pH is locally low. The pH around cancer is reported to be lower than normal tissue due to the organic acid produced by the vigorous metabolism of cancer cells, and the average pH is about 6.8. In addition, when the particles are absorbed into the cell to form an endosome, the pH of the endosome is known to be about 6.0 or less.

Thus, pH sensitive polymers have been prepared for drug delivery and disease treatment using locally low pH in cancer or inflammatory tissues. The pH-sensitive drug carrier refers to a type of carrier in which normal drug release of drug is rarely accumulated in the diseased area by EPR effect, and then the carrier collapses to maximize the release of the drug.

Existing pH-sensitive polymers have a problem that the pH sensitivity is significantly lower due to the change in pH, which is not practically available, or when the hydrophobic drug is encapsulated, high therapeutic efficacy cannot be expected.

Accordingly, the present inventors have developed a pH-sensitive drug carrier having nano-sized particles and containing a hydrophobic drug in cancer or inflammatory disease tissue, and then maximizing the release of anticancer drugs by disintegrating the carrier by a locally low pH environment. The present invention has been completed by developing nanoparticulate pH sensitive drug carriers for the treatment of cancer or inflammatory diseases, which can increase efficiency while minimizing the toxicity of drugs.

It is an object of the present invention to selectively accumulate in various cancer or inflammatory disease tissues, thereby increasing the therapeutic efficacy of the disease by releasing the drug at a high concentration within a short time as the nano-sized particles collapse at low pH conditions of the disease site. At the same time, the side effects of the drug are to provide a drug carrier consisting of a pH sensitive block copolymer incorporating a hydrophobic drug, which can be minimized.

In order to achieve the above object, the present invention provides a drug carrier consisting of a pH-sensitive block copolymer encapsulated with a hydrophobic drug. The pH sensitive block copolymer is an amphiphilic polymer having a hydrophilic moiety and a hydrophobic moiety, and has biocompatible or biodegradable properties.

The hydrophilic moiety is polyethylene glycol, poly (N-2- (hydroxypropyl) methacrylamide), poly (N-2- (hydroxypropyl) methacrylamide), poly (divinyl ether-co-maleic Unhydride) (poly (divinyl ehter-co-maleic anhydride)) or poly (styrene-co-maleic anhydride) (poly (styrene-co-maleic anhydride)), preferably acrylate or methacryl It is a polyethyleneglycol compound which has a single functional group of the rate.

The hydrophobic moiety is a poly (β-amino ester) (PAE), a poly (amido amine) (PAA) or a mixed copolymer (PAEA) thereof, preferably a poly (β-amino ester) (PAE). In addition, an amine compound or a diamine compound is present in the hydrophobic residue, and the amine compound is 3-methyl-4- (3-methylphenyl) piperazine, 3 methylpiperazine, 4- (bis- (fluorophenyl) methyl) Piperazine, 4- (ethoxycarbonylmethyl) piperazine, 4- (phenylmethyl) piperazine, 4- (1-phenylethyl) piperazine, 4- (1,1-dimethoxycarbonyl) piperazine, 4- (2- (bis- (2-propenyl) amino) ethyl) piperazine, methylamine, ethylamine, butylamine, hexylamine, 2-ethyl hexylamine, 2-piperidine-1-ethylamine, C -Aziridin-1-yl-methylamine, 1- (2-aminoethyl) piperazine (1- (2-aminoethyl) piperazine), 4- (aminomethyl) piperazine (4- (aminomethyl) piperazine), N N-methylethylenediamine, N-ethylethylenediamine, N-hexylethylenediamine, N-hexylethylenediamine, pycoliamine or adenine, and the diamine compound Silver piperazine, piperidine (pipe ridine), pyrrolidine, 3,3-dimethylpiperidine, 4,4'-trimethylene dipiperidine, N, N'-dimethyl ethylene diamine, N, N'-diethyl ethylene diamine, imidazolidine or diaplates.

The hydrophobic drug of the present invention is an anticancer agent or an anti-inflammatory agent, wherein the anticancer agent is paclitaxel, doxorubicin, retinoic acid, cis-platin, camptothecin, 5-FU, Docetaxel, Tamoxifen, Anasterozole, Anasterozole, Carboplatin, Topotecan, Velotecan, Irinotecan, Gleevecan and Gleevec (gleevec) vincristine, and the anti-inflammatory agents are aspirin and salicylates, ibuprofen, naproxen, fenoprofen, indomethacin ), Phenyltazone, mesotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, celecoxib, valdecoxib Sieve (valdecoxib), it will be selected from the group consisting of lead mesyul (nimesulide), cortisone (cortisone), and corticosteroids (corticosteroid).

The pH-sensitive drug carrier encapsulated with the hydrophobic drug of the present invention has a property of rapidly disintegrating the particles at a pH 7.2 or lower, which is a locally low pH of a cancer or inflammatory disease site, and the cancer disease includes lung cancer, Uterine cancer, cervical cancer, prostate cancer, head and neck cancer, pancreatic cancer, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney cancer, colon cancer or rectal cancer, wherein the inflammatory disease is rheumatoid arthritis, osteoarthritis or arteriosclerosis.

Hereinafter, the present invention will be described in detail.

The drug carrier of the present invention is composed of a nano-sized pH-sensitive block copolymer, and the drug carrier is enclosed with an anticancer agent or an anti-inflammatory agent, which maintains the particle form under normal pH 7.4 conditions, but the drug is not released. Alternatively, at low pH conditions of the site of inflammatory disease, the drug may be selectively released to improve the therapeutic efficacy of the cancer or inflammatory disease and to minimize drug toxicity. Accordingly, the present invention provides drug delivery therapeutics that can be used for the treatment of various cancers or inflammatory diseases.

The pH-sensitive block copolymer is composed of amphiphilic polymer nanoparticles, and the polymer nanoparticles may form nano-sized self-assembly or self-aggregates through a balance between hydrophobicity and hydrophilicity. And may selectively accumulate along blood vessels developed in various cancer or inflammatory disease tissues. In addition, it is easy to encapsulate various anticancer agents or anti-inflammatory agents in the pH-sensitive polymer nanoparticles, and may be applied to the treatment of cancer and inflammatory diseases.

The hydrophilic polymer is a biodegradable compound having a known hydrophilicity can be used without limitation, preferably poly (N-2- (hydroxypropyl) methacrylamide) (poly (N-2- (hydroxypropyl) methacrylamide) Poly (divinyl ehter-co-maleic anhydride) (poly (styrene-co-maleic anhydride)), poly (styrene-co-maleic anhydride) Or synthesized from dextran, chitosan, glycol chitosan, poly-L-lysine and poly-aspartic acid groups More preferably, it is a polyethyleneglycol type compound, More preferably, it has a single functional group (monofuncational), such as an acrylate or a methacrylate, in the terminal of a polyethyleneglycol type compound.

The hydrophobic moiety is a hydrophobic moiety polymer may be any polymer having biocompatibility / biodegradability, preferably a poly (amino acid) compound having both hydrophobicity and pH sensitivity, and non-limiting examples thereof include poly (β-amino Ester) (PAE), poly (amido amine) (PAA), or mixed copolymers thereof (PAEA) and the like, of which poly (β-amino ester) (PAE) is most preferred.

The drug carrier particles made of the pH-sensitive block copolymer have excellent biocompatibility / biodegradability in vivo, and have excellent stability in vivo, and thus have high biodistribution in the blood and accumulate in cancer or inflammatory disease tissues for a sufficient time. There is a characteristic.

As hydrophobic drugs bound to the hydrophilic polymer, paclitaxel, doxorubicin, retinoic acid, cis-platin, camptothecin, 5-FU, docetaxel ), Tamoxifen, Anasterozole, Carboplatin, Topotecan, Verotecan, Irinotecan, Gleevec, Vincristine, etc. Anticancer agents, aspirin and salicylates, ibuprofen, naproxen, fenofene, fenoprofen, indomethacin, phenylbutazone, Mesotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valecoxib, valdecoxib, nimesulide nimesulide, cortisone, nose The anti-inflammatory agent such as a corticosteroid (corticosteroid), it is preferable that the encapsulated drugs with hydrophobicity.

The pH-sensitive drug carrier in which the drug is encapsulated maintains the nano-sized particles in the normal pH range of pH 7.2 to pH 7.4, but the drug is not released, but at pH 7.2 or lower, which is an abnormal condition such as cancer or inflammatory disease tissue, May collapse and release the drug. In addition, the cells may be absorbed into the cell to disintegrate particles at pH 6.0 or lower of the endosome due to endocytosis, thereby releasing the drug.

Cancers treatable with the drug delivery system of the present invention are lung cancer, uterine cancer, cervical cancer, prostate cancer, head and neck cancer, pancreatic cancer, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney cancer, colon cancer or rectal cancer, and the inflammatory disease is rheumatoid Arthritis, osteoarthritis or arteriosclerosis.

In addition, the present invention can be applied to other applications such as cancer and inflammatory diseases by appropriately changing the components of the block copolymer, their molar ratio, molecular weight and functional groups in the block, folic acid (folic acid), RGD-based protein By designing a target-oriented micelle by labeling the aptamer, or the like, it can be usefully applied.

In addition, in the present invention, by varying the formation conditions, functional groups, and the like of the pH-sensitive block copolymer, it is possible to easily control the rate of drug degradation in vivo of the pH-sensitive block copolymer particles, through which appropriate drug delivery must be made. The drug may be delivered selectively to the target location.

In a preferred embodiment of the present invention, a pH-sensitive block copolymer composed of a hydrolyzable polyethylene glycol hydrophilic moiety and a poly (β-amino ester) (PAE), in which a hydrophobic anticancer agent or an anti-inflammatory agent is encapsulated in a nanosized particle composed of the hydrophilic moiety. will be. The pH sensitive block copolymer which can enclose such a hydrophobic drug can be represented by following General formula (1).

General formula (1)

In the general formula (1), the pH-sensitive block copolymer means a repeating structure of a hydrophilic residue polyethylene glycol and a poly (β-amino ester), and in the structure of the hydrophobic residue, poly (β-amino ester), R represents various alkyl chains. It means structure.

Although the molecular weight of the polyethylene glycol series compound which is a hydrophilic residue in the said General formula (1) does not have a restriction | limiting in particular, The range of 500-5,000 is preferable. Diamine compounds present in the structure of the hydrophobic moiety poly (β-amino ester) include piperazine, piperidine, pyrrolidine, 3,3, -dimethylpiperidine (3,3-dimethylpiperidine) ), 4,4'-trimethylene (dipiperidine), N, N'-dimethylethylenediamine, N, N'-diethylethylenediamine, imidazoline or diazepan.

R in the general formula (1) is an alkyl chain containing 1 to 20 carbon atoms.

The drug carrier, which is composed of pH-sensitive block copolymers based on Formula (1), is made of nano-sized particles in self-assembled or self-aggregated form in aqueous solution, and the size ranges from tens to hundreds of nanometers. Have

Drugs that can be encapsulated in nano-sized particles of pH-sensitive polymer drug carriers include various anticancer or anti-inflammatory drugs in clinical trials or in clinical use, including paclitaxel, doxorubicin, and retinoic acid ( retinoic acid family, cis-platin, camptothecin, 5-FU, docetaxel, tamoxifen, anasterozole, carboplatin, and topotecan anticancer drugs such as topotecan, belotecan, irinotecan, gleevec, vincristine, aspirin and salicylates, ibuprofen and naprosen ( naproxen, fenoprofen, indomethacin, phenyltazone, phenyltazone, mesotrexate, cyclophosphamide, mechlorethamine, dexamethasone anti-inflammatory agents such as methasone, prednisolone, celecoxib, valdecoxib, valdecoxib, nimesulide, cortisone, corticosteroid, and these drugs are hydrophobic As it is easy to inject drugs, it is possible to treat cancer or inflammatory diseases.

The drug-sensitive pH-sensitive drug carriers can easily disintegrate and release the drug under acidic conditions below pH 7.2. In addition, the drug-encapsulated pH-sensitive drug carrier has high selectivity to diseased tissue due to the EPR effect of cancer or inflammatory tissue, compared to low-molecular weight drugs, and has excellent accumulation efficiency at the disease site, and has a low molecular weight in vivo. It is significantly increased over the drug, improving the efficacy of treating cancer or inflammatory disease, and reducing the toxicity of the drug.

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Experimental Examples. However, the following Examples and Experimental Examples are only examples of the present invention, and the scope of the present invention is not limited thereto.

Example  One. Doxorubicin Enclosed  pH Sensitive Drug Delivery Preparation

100 mg of pH sensitive polymer, MPEG-HPAE, was dissolved in 20 ml of chloroform / methanol (1: 1, v / v) cosolvent. 10 mg of doxorubicin was dissolved in 5 ml of chloroform / methanol (1: 1, v / v) co-solvent containing triethylene amine, and then added to a solution containing pH sensitive polymer and stirred for 10 minutes. The mixed solution was placed in a 100 ml round flask and the solvent was evaporated completely using a stirred distillation. At this time, the polymer and doxorubicin spread evenly on the wall of the flask to form a thin film. After 10 ml of distilled water was added to the flask and stirred, the unsealed drug was removed by filtration and then lyophilized.

After lyophilization, 2 mg of doxorubicin-encapsulated pH-sensitive drug carrier was dissolved in chloroform / methanol (1: 1, v / v) cosolvent, and the efficiency of doxorubicin-encapsulation in pH-sensitive polymer was measured using a UV-vis spectrometer. Measured using. In addition, particle size and shape before and after doxorubicin were analyzed by dynamic light scattering apparatus and transmission electron microscopy.

The doxorubicin-encapsulated pH-sensitive drug carrier is prepared by the doxorubicin is encapsulated in the drug carrier by the hydrophobic interaction of the pH-sensitive polymer block copolymer consisting of hydrophilic and hydrophobic residues, the production principle of which is shown in Scheme 1 As shown.

Experimental Example  1. Particle size analysis of drug carriers

The size of drug carrier micelle particles before and after doxorubicin encapsulation in micelle particles composed of pH sensitive polymers was analyzed by dynamic light scattering device and transmission electron microscope.

As a result of performing the experiment, as shown in FIGS. 2A to 2D, the size of the micelle composed of MPEG-HPAE (see FIG. 2A) and MPEG-OPAE (see FIG. 2C), which is a pH-sensitive polymer without doxorubicin, is It was measured at 42 nm and 53 nm, respectively. In addition, doxorubicin-encapsulated DOX-MPEG-HPAE (see FIG. 2B) and DOX-MPEG-OPAE (see FIG. 2D) showed particle sizes of 62 nm and 94 nm, respectively. Also, as a result of analysis by transmission electron microscope, all particles showed spherical particle shape.

Experimental Example  2. Doxorubicin Enclosed  Drug Release of pH-Sensitive Drug Carriers

Drug release experiments of DOX-MPEG-HPAE and DOX-MPEG-OPAE, the pH-sensitive drug carriers containing doxorubicin-encapsulated prepared in Example 1, were drug-released in a PBS solution of pH 7.4 and a PBS solution of pH 6.4.

As a result of the experiment, as shown in FIG. 3, about 20% of doxorubicin was released from the micelle particles under physiological pH 7.4. However, at low pH conditions such as pH 6.4 and pH 5.8, doxorubicin was released at 65% or more within 6 hours. This is because the doxorubicin-encapsulated drug carrier is stable at pH 7.4 and shows a slow drug release rate.However, at low pH, hydrogen ion (H +) binds to the amine of dipiperidine in the hydrophobic moiety of the polymer and is hydrogenated. Doxorubicin is released at a rapid rate as the drug carrier collapses due to the positive charge repulsion. In other words, the pH-sensitive drug carriers doxorubicin-encapsulated quickly release the drug under acidic conditions.

Experimental Example  3. Doxorubicin Enclosed  pH-sensitive drug carriers Intracellular Doxorubicin Absorption

Doxorubicin-encapsulated pH-sensitive drug transporter, DOX-MPEG-HPAE particles were observed by fluorescence microscopy that doxorubicin is absorbed into cells due to the disruption of the drug transporter at physiological pH 7.4 and extracellular pH conditions of acidic conditions.

As a result of performing the experiment, as shown in FIG. 4, the intracellular uptake of doxorubicin was less at pH 7.4, but the uptake of doxorubicin was higher in the cell at pH 6.4. As a result, it was found that the drug carrier collapsed under acidic conditions and absorbed at a high concentration within a short time.

Experimental Example  4. Doxorubicin Enclosed  pH-sensitive drug carriers Intracellular Doxorubicin Absorption

The anticancer efficacy of pH-sensitive drug carriers in which doxorubicin-encapsulated C57 / BL6 mice transplanted with B16F10 cancer cells were repeatedly administered to the tail blood vessel was evaluated.

As a result of the above experiment, as shown in FIGS. 5A to 5C, the drug delivery agent of DOX-MPEG-HPAE containing doxorubicin was improved in cancer growth inhibition effect than the doxorubicin-only group (FIG. 5A), rather than doxorubicin itself. The weight loss rate of mice in the group to which the DOX-MPEG-HPAE drug carrier was administered was low (FIG. 5B), and the survival rate of the mice was significantly higher when the DOX-MPEG-HAPE drug carrier was administered (FIG. 5c). In other words, the doxorubicin-encapsulated pH-sensitive drug carriers were found to improve cancer treatment efficacy while lowering the toxicity induced by doxorubicin.

As described above, the present invention relates to a drug carrier comprising a hydrophilic moiety and a pH sensitive block copolymer having both hydrophobic moieties enclosed with a hydrophobic drug, wherein the drug carrier of the present invention is localized to a cancer or inflammatory disease site. The low pH easily disrupts the drug carrier, delivering a particularly high concentration of the drug to the disease site, thereby increasing the efficacy of the drug and at the same time significantly reducing its toxicity to the drug itself.

Since the pH-sensitive drug carrier of the present invention has a hydrophobic moiety on the center of the particle, it can easily encapsulate various anti-cancer drugs or inflammatory drugs which are currently being developed or applied to the clinic, thereby preventing cancer or inflammatory diseases. It is a very useful invention for the treatment of diseases.

Claims (13)

A drug carrier comprising a hydrophilic moiety and a hydrophilic moiety and a hydrophilic moiety having a pH-sensitive block copolymer. The method of claim 1, wherein the hydrophilic moiety is polyethylene glycol, poly (N-2- (hydroxypropyl) methacrylamide), poly (N-2- (hydroxypropyl) methacrylamide), poly (divinyl ether Drug carriers, which are poly (divinyl ehter-co-maleic anhydride) (poly) or poly (styrene-co-maleic anhydride) (poly (styrene-co-maleic anhydride)) . The drug carrier of claim 2, wherein the hydrophilic moiety is a polyethylene glycol compound having a single functional group of acrylate or methacrylate. The drug carrier of claim 1, wherein the hydrophobic moiety is a poly (β-amino ester) (PAE), a poly (amido amine) (PAA), or a mixed copolymer thereof (PAEA). The drug delivery carrier of claim 4 wherein the hydrophobic moiety is a poly (β-amino ester) (PAE). The drug carrier according to claim 4, wherein an amine compound or diamine compound is used for the hydrophobic moiety. The compound of claim 6, wherein the amine compound is 3-methyl-4- (3-methylphenyl) piperazine, 3 methylpiperazine, 4- (bis- (fluorophenyl) methyl) piperazine, 4- (ethoxycarb Bonylmethyl) piperazine, 4- (phenylmethyl) piperazine, 4- (1-phenylethyl) piperazine, 4- (1,1-dimethoxycarbonyl) piperazine, 4- (2- (bis- ( 2-propenyl) amino) ethyl) piperazine, methylamine, ethylamine, butylamine, hexylamine, 2-ethyl hexylamine, 2-piperidin-1-ethylamine, C-aziridin-1-yl-methyl Amine, 1- (2-aminoethyl) piperazine (1- (2-aminoethyl) piperazine), 4- (aminomethyl) piperazine, N-methylethylenediamine ), N-ethylethylenediamine, N-hexylethylenediamine, N-hexylethylenediamine, pycoliamine or adenine (adenine) drug carrier. The diamine compound according to claim 6, wherein the diamine compound is piperazine, piperidine, pyrrolidine, 3,3-dimethylpiperidine, 4,4'-trimethylene di A drug carrier, which is piperidine, N, N'-dimethyl ethylene diamine, N, N'-diethyl ethylene diamine, imidazolidine or diazepan. According to claim 1, wherein the drug is paclitaxel (paclitaxel), doxorubicin (doxorubicin), retinoic acid (cis-platin), cito-platin (camptothecin), 5-FU, Docetaxel (Docetaxel), Group consisting of Tamoxifen, Anasterozole, Carboplatin, Topotecan, Verotecan, Irinotecan, Gleevec and Vincristine Drug delivery system that is selected from the cancer drug. The drug of claim 1, wherein the drug is aspirin and salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbuta Phenyltazone, mesotrexate, cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib, valecoxib, valdecoxib The drug delivery agent is an anti-inflammatory agent selected from the group consisting of nimesulide, nimesulide, cortisone and corticosteroid. The drug delivery carrier according to claim 1, wherein the drug delivery carrier has the property of rapidly disintegrating the particles at pH 7.2 or lower, which is a locally low pH of a cancer or inflammatory disease site. The drug carrier according to claim 2, wherein the cancer disease is lung cancer, uterine cancer, cervical cancer, prostate cancer, head and neck cancer, pancreatic cancer, brain tumor, breast cancer, liver cancer, skin cancer, esophageal cancer, testicular cancer, kidney cancer, colon cancer or rectal cancer. The drug delivery system according to claim 2, wherein the inflammatory disease is rheumatoid arthritis, osteoarthritis or arteriosclerosis.

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